OVERALL DESCRIPTION (provided by applicant): The recruitment of eosinophils, basophils, and Th2 lymphocytes, and their subsequent activation and release of inflammatory mediators are hallmarks of allergic inflammatory responses to local allergen exposures. This unique series of events reflects the existence of specific, regulated mechanisms for control of leukocyte recruitment. In this proposal, we hypothesize that the exact molecular mechanisms involved in these responses depend on the organ involved. Projects will examine mechanisms that facilitate tissue-specific and leukocyte-specific influx during allergic inflammation. Studies by our laboratories and others suggest that pathways for leukocyte recruitment can be dramatically potentiated by the inflammatory cytokine TNFa. Thus, another central hypothesis of this proposal is that TNFa is a powerful amplifier of the allergic inflammatory response. All three Projects involve human translational research with techniques ranging from molecular and cell biology to pharmacology in models of allergen challenge of the skin, nose and lungs. Project 1 will examine the role of TNFa in the allergic late phase response by treating allergic subjects with the soluble TNF receptor Etanercept (Enbrel) prior to allergen challenge, and will define pathways responsible for trafficking of inflammatory leukocytes into each organ. Project 2 will focus on mechanisms of basophil recruitment and activation in allergy by analyzing chemokines, chemokine receptors, and adhesion pathways mediating cell migration in vitro and in vivo, and how recruited basophils subsequently activate tissue resident cells (e.g., respiratory epithelium). Project 3 will examine mechanisms of Th2 cell and antigen-specific T cell recruitment to the lung following allergen challenge by comparing functional and phenotypic characteristics of cells in blood, BAL fluids, and biopsies. All sections are highly integrated; for example, Project 1 will provide specimens to Project 2 for analysis of basophils and their recruitment factors and to Project 3 for analysis of T cells. Cores for administration and tissue processing are also included. Although this is a new AADRC proposal, the investigators have a longstanding record of collaboration. These projects should improve our understanding of the mechanisms involved in allergic inflammation. We expect that the results of these studies will be of great relevance to human disease pathogenesis and the development of new therapeutics.